PTEN and p53 are the most frequently mutated tumor suppressors in human cancer, including gliomas. Recent evidence shows that wild-type PTEN and wild-type p53 (wt-p53) enhance each other's tumor suppressive functions. Wt-p53 induces PTEN gene transcription and wt-PTEN protects wt-p53 protein from degradation. We recently found, for the first time, that PTEN has unexpected tumor promoting properties in some glioma cells and tumor xenografts. We have preliminary evidence that PTEN acquires these unexpected tumor promoting properties by enhancing the half-life and oncogenic effects of gain-of-function p53 mutants (mut-p53). Based on these findings, we formulate the following novel hypothesis: PTEN tumor suppressor can exhibit tumor promoting properties in the setting of gain-of-function mut-p53. Therefore, therapeutic strategies that aim at restoring PTEN expression or function could lead to varying effects that depend on the mutational status of p53. To test this hypothesis and its prognostic, mechanistic, functional and therapeutic implications, we propose the following studies: In aim #1, we will use a large number of banked human glioblastoma specimens to determine the association between the combined PTEN/p53 mutational status and clinical outcome. In aim #2, we will investigate the mechanism through which PTEN regulates mut-p53 protein levels and function. In aim #3, we will assess the in vivo effects of restoring PTEN to glioma tumors with varying p53 mutational status. In aim #4, we will determine if small molecule modulators of p53 can reverse the tumor promoting effects of PTEN in mut-p53 cells and tumors. The results from all aims will be assessed for their consistency with the hypothesis. Successful completion of the studies proposed in this application would: 1) establish the combined PTEN/p53 status as a prognostic parameter (aim 1), 2) uncover previously unknown mechanistic and functional interactions between PTEN and mut-p53 (aim 2), 3) determine conditions and strategies for a successful therapeutic restoration of PTEN (aim 3), and 4) have important clinical implications for the use of small molecule modulators of p53 by identifying a subset of tumors that are more sensitive to these drugs and providing a rationale for their combination with PTEN restoration (aim 4). PUBLIC HEALTH RELEVANCE: We recently discovered that the tumor suppressor PTEN can have surprising tumor promoting properties. We have evidence that these unexpected properties depend on mutations of the tumor suppressor p53. We propose to study the interactions between PTEN and p53 mutations. We also propose to determine the conditions and test new strategies for successful tumor suppressor restoration to human tumors. The findings will have important implications on determining patient prognosis and developing new therapies against human cancers.